mTORC1 Regulates Glutamine Metabolism

Glutamine, the most abundant amino acid in the body, is a key source of nitrogen and metabolites for proliferating cells. Cancer cells are particularly dependent on glutamine to fulfill their increased biosynthetic demands. Activation of mTOR complex 1 (mTORC1), a key regulator of nutrient uptake and cellular proliferation, has recently been linked to glutamine addiction in cancer cells, but whether mTORC1 itself regulates glutamine metabolism remains unclear. Csibi and colleagues observed that mTORC1 activation stimulated glutamine uptake, whereas inhibition of mTORC1 activity suppressed a critical step in glutaminolysis, the conversion of glutamine to α-ketoglutarate. Consistent with these findings, the activity of glutamate dehydrogenase (GDH), one of the enzymes responsible for glutamine conversion, was specifically reduced in response to mTORC1 inhibition due to upregulation of the mitochondrial sirtuin SIRT4, which negatively regulates GDH through ADP-ribosylation. In cells with increased mTORC1 signaling, mTORC1 negatively regulated SIRT4 expression by promoting the ubiquitination and proteasomal degradation of cAMP responsive element binding protein 2 (CREB2, also known as activating transcription factor 2). Forced expression of SIRT4 in cells with elevated mTORC1 activity led to decreased glutamine uptake in association with decreased cell proliferation and tumorigenicity, not only suggesting that SIRT4 has tumor suppressor activity but also indicating that targeting glutaminolysis might inhibit the growth of mTORC1-hyperactive cells. Indeed, pharmacologic inhibition of GDH or glutaminase synergized with glycolytic inhibitors to specifically induce cell death in cells with increased mTORC1 signaling. Together, these results point to a central role for mTORC1 in regulation of cellular glutamine utilization and raise the possibility that mTORC1-driven cancers may be especially sensitive to inhibition of glutamine metabolism.

Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 2013;153:840–54.